Therapeutically useful heterocyclic compounds



halogen,

Patented Nov. 23, 1943 UNITED STATES PATENT OFFICE THERAPEUTICALLY USEFUL HETERO- CYCLIC COMPOUNDS Arthur James Ewins, Gidea Park, Romford, and

Montague Alexander Phillips, Romford, England, assignors to May & Baker, Limited, London, England, a company of Great Britain and Northern Ireland No Drawing. Original application November 1,

1938, Serial No.

238,164, now Patent No.

2,275,354, dated March 3, 1942. Divided and this application April 19, 1940, Serial No. 330,529. In Great Britain, Australia, New Zealand, and India November 29, 1937 Claims. (c1. 250296) This is a division of co-pending application Ser. No. 238,164, filed November 1, 1938, for The mumOsmmm-a in which R represents a heterocyclic nucleus of the pyridine, quinoline or isoquinoline series and therapeutically useful in which R1 may be hydrogen, acyl, alkyl, aryl or aralkyl, and R2 may be hydrogen or alkyl and R3 may be hydrogen, alkyl, aryl, aralkyl oracyl.

According to the present invention these compounds may be prepared by various methods which may be summarised as follows:

' A. Derivatives in which RlRZ and R3 are hydrogen atoms may be prepared by condensing a compound of the type p-XCsI-IrY with a compound of the type ZR in which R is a pyridine, quinoline or isoquinoline residue, and when Y is $0201, X is NHz and when Y is SOZNHZ, Z is a to form compounds of the type XC6H4SO2NHR which can be'readily converted into compounds of the type NHzCsHrSOzNI-IR. X therefore represents a group such as an acylamino group, 2, nitro group, an azo group linked to an organic radicle, or a halogen, which groups may be converted into an amino group by hydrolysis in the first mentioned case, by reduction in the secondand third-mentioned cases, or by the action of ammonia in the fourth case.

B. similarly derivatives in which R1 and R2 are hydrogen atoms, and R3 an aryl, alkyl, or aralkyl group may be prepared by condensation of compounds of the type p-XCsI-RY with compounds of the type ZR. in which when Y is S0201, Z is NHR3 and when Y is SOzNHRz, Z is a halogen to form compounds of the type p-XCsI-hSOzNRzR, from which the required amino products may be obtained as described in paragraph A. r

C. Derivatives in which R1 is hydrogen or an alkyl or acyl group, R2 is an alkyl, aryl, or aralkyl group and R3 is either hydrogen or an alkyl, aryl, or aralkyl group may be prepared by condensing a compound of the type R1R2I-LC$H4Y with a compound of the type ZR in which R is the' residue of a pyridine, quinoline 0r isoquinoline base, and when Y is SOzCl, Z is NHRs and when Y is SOzNHRs, Z is a halogen.

D. Derivatives in which R1 is a hydrogen or alkyl, R2 is an alkyl, and R3 is hydrogen or an alkyl, aryl or aralkyl group may be prepared from condensation products of the types described in A and B in which X is a'halogen by reacting on the respective halogenated condensation products with a primary or secondary amine instead of with ammonia.

E. Acyl, alkyl, aryl or aralkyl derivatives of compounds prepared by the foregoing methods containing one or more replaceable hydrogen atoms attached to nitrogen may be prepared by known methodssuch as by the use of acyl, alkyl,

aryl, or alalkyl halides or alkyl sulphates.

Besides using compounds of the type 10-25061-1480201, various chemically equivalent processes may be used instead, such as the use of theanhydrides (p-XCaHrSOzMO or the bromides .p-X.C6H4SO2B1.

The following examples illustrate how the invention may be carried out in practice, but it is to be understood that the invention is in no way limited to the details given in these examples:

Example 1 To 16 grams of fi amino-quinaldine dissolved in 30. cc. of dry pyridine is added 24 grams of p-acetylamino-benzene-sulphonyl chloride. After heating on a steam bath for 1 hour and diluting with water, the crystalline precipitate is collected, washed and purified by precipitation of the solution in normal sodium hydroxide solution with excess of boiling 2N acetic acid. It melts at 272 C.

This is converted to the amino compound by refluxing for so minutes with ten times its weight of 2N sodium hydroxide solution. Onacidifica- '20Ci-240 for 1 hour.

formed by alkaline hydrolysis.

.2-amino-pyridine in 25 cc. of pyridine.

tion to litmus, the base is obtainedas a gum which rapidly crystallises. Alternatively, hydrolysis may be effected by heating under reflux with 12 parts of dilute 15% hydrochloric acid for 1 hour and adding 50% sodium hydroxide solution until the solution is still acid to litmus but not to Congo Red. The precipitated product is purified by solution in boiling alcohol and precipitation with water. Meltingpoint 252 0.

Example r j To a solution of 4.7 grams of 2-amino-pyridine in 10 cc. of dry pyridine is added, with cooling,

12 grammes of p-nitro-benzene-sulphonyl-chloride. An energetic reaction results: when this is over, the mixture is diluted with water, (200 cc.) and the precipitate of Z-(p-nitro-benzenesulphonamido) -pyridine collected. Meltin point 185 C. a

The nitro compound (1.4 grams) is dissolved in about 5 cc; of 2 sodium hydroxide solution and the suspension of Na salt formed on standing is added at 20 C. to a paste of ferrous hydroxide from 10 grams ferrous sulphate (hydrated) in 30 cc. water and 3 grams sodium hydroxide in 5 cc. of water. After standing (1 hour) the mixture is filtered from ferric hydroxide and the filtrate acidified with acetic acid. The 2-(pamino-benzene-sulphonamido) -pyridine melts at Example 4 16.5 grams of p-chlorobenzene-su1phonyl-chloride is added to a solution of 7 grams of 2-aminopyridine in 20 cc. of pyridine.

precipitated 2- (p-chlorobenzene-sulphonamido) pyridine is collected, washed and dried, in. pt. 186 C. This is then heated in a closed vessel with 4 parts by weight of concentrated aqueous ammonia in the presence of about 1 part by weight of cuprous chloride for 13 hours at 150- V The excess of ammonia is removed and on dilution with water, 2- (p-amino-benzene-sulphonamido) -pyridine is obtained and may be purified by crystallisation from water.

Example 5 A mixture of 21.4 grams of p-acetylaminobenzene-sulphonamide, 13.0 grams of anhydrous potassium carbonate, 1.0 gram of copper powder and 15.8 grams of 2-bromo-pyridine is heated at The melt is dissolved in boiling water and filtered. On acidification with acetic acid, 2(p-acetylaminobenzene sulphonamido)-pyridine, 111. pt. 224 is obtained from which 2(p-amino-sulphonamido) pyridine is Example 6 grams of p-nitro-benzene-sulphonic acid 'anhydride (prepared by the action of thionyl chloride on p-nitro-benzene-sulphonic acid dihydrate) are added to-a solution of 5 grams of The reaction mixture becomes warm and a precipitate of 2-(p-nitro-benzene-sulphonamido) pyridine is formed. The reaction mixture is diluted with water and dried. Melting point 195 C.

This compound on reduction according to the method of pl 3 yields 2-(p-amino-benzene- *sulphonamido) -pyridine.- V

After heating at 90 C. for minutes, water is added and the short time.

Example 7 2.5 grams of 2-(p-amino-benzene-sulphonamido)-pyridine is suspended in 10 cc. of pyridine at laboratory temperature and 2 grams p-nitro-benzoyl chloride is added. The mixture 'is allowed to cool, diluted with water, and the precipitated 2lp-(p -nitro benzoyl amino)-benzene sulphonamidol pyridine filtered oif, washed 7 with water and dried. Melting point 272.

Example 8 5.4 grams of 5-amino-S-methoxy-quinoline is dissolved in 10100. of pyridine, 7.3 grams of p acetylamino benzene sulphonyl chloride added, and the mixture heated at C. for a Water is then added and the precipitated S-(p-acetylamino benzene sulphonamido)-8 methoxy quinoline filtered off and crystallised from dilute alcohol. Melting point 185 C. t

On hydrolysis of this acetyl compound by boiling with 10 parts of 2N sodium hydroxide followered by neutralisation to Congo Red, 5-(pamino-benzene-sulphonamid0) -8-methoxy quinoline is obtained, which recrystallised from water, melts at 228-230 C.

Emample 9 6.6 grams of 2:6' diamino-pyridine is dissolved in 40 cc. of pyridine and 29.0 grams of p-acetylamino-benzene-sulphonyl chloride added. When the reaction mixture has cooled, water is added and the precipitated 2:6 di(p-acetylamino-benzene-sulphonamido) pyridine crystallised by solution in boiling alcohol sodium hydroxide and reprecipitation with 'hot acetic acid. Melting point 275 C. On hydrolysis by boiling for 1 hour with cc. of 2N caustic soda solution, and acidifying with dilute acetic acid 2:6 di(pamino-benzene sulphonamido)-pyridine is precipitated. The crude product is purified by solu- ,water and crystallised from dilute alcohol. Melting point 304 C. r

On hydrolysis of this compound by boiling for 1 hour with 10 parts of dilute caustic soda and subsequently acidifying with dilute acetic acid 2 hydroxy-4 methyl 7-(p-amino-benzene-su1- phonamido) -quinoline is precipitated. After purification by solution in hot dilute sodium hydroxide and re-precipitation by acidifying with hot acetic acid the pure compound melts at 289 c. v Example 11 14 grams of 2 amino-pyridine-3-carboxylic acid is suspended in 100 cc. of pyridine and 24 grams of p-acetyl-amino-benzene sulphonyl chloride added; The mixture is heated on the water bath for 10 minutes, diluted with water, and the precipitated 3 car-boxy-Z-(p-acetylamino benzene-'sulphonamido)-pyridine recrystallised .from alcohol. M. pt. C. (dec.) On hydrolyamsaaai :sis by boiling with .10 .parts of dilute sodium hydroxide solution :and acidifying withkdilute .acetic .acid .3 oarboxy-2-(p-amino benzeneesulphonamido) epyridine is precipitated, which is obtained crystalline j-by solution in .hot dilute sodium hydroxide and acidification with iacetic acid. Melting 'point 176.179 C.

Example 12 .103 grams of 2-amino-6-methyl zpyridine ;is

Example 13 .14 grams Qf S-aminQ-quinoline are dissolved in 30 oo. of quinoline and .24,grams of p-acetylamino-benzeneesulphonyl chloride added. The mixture is heated ona steam bath .for about 30 minutesanddiluted with 300 .cc.-of water when 6- p-acetylamino-benzene-sulphonamido) -quinoline is precipitated, filtered off, Washed with water and recrystallised. Melting point 275 C. On hydrolysis with ten parts of boiling 2N caustic-soda solution for 1 hour and acidifying with dilute acetic acid 6-(p-amino-benzene-sulphonamido) quinoline is obtained. After "crystallisation from dilute alcohol it melts at 200 C.

Example 14 457 grams of 2-amino pyridine are dissolved in '20 cc. of benzene, 12 .grams of p-acetyla-minobenzene-sulphonyl chloride added and the mixture allowed to stand. The solid which separates is filtered off and boiled for 1 'hour with 90 cc. of

2N caustic soda solution. On acidification with dilute acetic acid Z-(p-amino-benzene sulphonamido) -pyridine is precipitated and recrystallised from acetone. Melting point '1-90 0.

Example 15 1 2 grams of 2-(p chlor-loenzene-sulphonamido) pyridine (Example 4,) or'2 grams of 2 p-'brom-" benzene-sulphonamido) pyridine (obtained in a similar manner from p-brom-benzene-sulphonyl-chloride and 2 amino py-ridine') is heated in a closed vessel with 8 cc. of a *per cen't. aqueous solution of methylamine, and 0.1 gram of cuprous chloride for 12 hours at 150 C." After cooling, the reaction mixture is diluted with water and the precipitated 2 (pemethyl-amino-benzenesulphonamido) pyridine purified by recrystallisation from alcohol. Melting point 154 C.

' Example 16 -9 grams of 22-4; dinitro-diphenylam inol -sulphonyl chloride prepared by the action of phosphorous pentac'hloride on the sodium salt of the corresponding sulphonic acid is added to a solution of 2.3 grams of 2-'ami no-pyridine in 20 cc. of pyridine. When the reaction is complete, water is added and the precipitated 2-(p-(2:4 dinitro-phenylamino) -benzene sulphonamido) pyridine filteredofi, washedand crystallised from its solution in hot dilute alcoholic caustic soda by addition .of 150 per lcent. acetic acid. Melting point 230-233 C.

Example 17 5 :grams of .2-.(p-chlorbenzene-s111phonamid0 pyridine are heated in a closed vessel with 20 cc. of a 30 per cent. aqueous solution of dimethylamine and 0.25 gram of cuprous chloride at 170 C.'for 12 hours. After cooling, the contents of the tube are diluted with water and the precipitate extracted with cold dilute hydrochloric acid. Sodium acetate is then added to the acid extract and the precipitated 2-(p-dimethylamino-benzene sulphonamido) -pyridine recrystallised from alcohol. 'It melts at 2l8-220 C.

. Example .1 8

0 15 grams of 4-amino-pyridine are dissolved in '80 cc. of water, 40 grams of p-acetyl-amino-benzene-sulphonyl chloride added followed by 10 grams of anhydrous sodium carbonate. The mixture is stirred at room temperature for 1 hour and the precipitated 4-(p-acetylamino-benzene sulphonamido)-pyridine 'filtered off and washed with water. Crystallised from alcohol it melts .at 252 C. Hydrolysis by boiling with 400 .cc. of 2N caustic soda solution for 1 hour and acidifying the resulting solution with dilute acetic acid. gives 4-(p-amino-benzene-sulphonamido) pyridine which on recrystallisation from dilute alcohol .melts at 240 C.

Example 19 21.; grams of p-acetylamino-benzene-sulphonamide, 13.5 grams of potassium carbonate, 1.0 gram of copper powderand 16.4 grams of 2-chloroquinoline are heated together under reflux for 1 /2 'hours at 240-250 C. The cooled reaction mass is extracted with boiling water filtered and the filtrate acidified with acetic acid when crude 2- (p-acetylamino -benz ene-sulphonamido) quinoline is precipitated.

On hydrolysis by boiling with 160 cc. of 2N sodium hydroxide "for 1 hour and acidifying the resulting solution with acetic acid 2-(p-aminobenzene-sulp'honamido) quinoline is obtained which after re-solution in boiling dilute alkali and acidifying with hot acetic acid is obtained crystalline. Melting point 193-195 C.

Example 20 17 grams of 2-(p-dimethylaminobenzene-sulphonamido) -pyridine (Example 17) is dissolved in 60. cc. of 2N sodium hydroxide solution, and 7 gramsof'dimethyl sulphate added with stirring to the cooled solution. 2-(p-dimethylaminobenzene-sulphonmethylamido) pyridine separates as an oil which rapidly solidifiesand when recrystallised from dilute acetic acid melts at 155 C.

\ Example 21 20 grams of 2-(p-amino-.benzene-su1phonamido) -pyridine is dissolved in 120 cc. of 2N sodium hydroxide solution and 8 vcc. of dimethyl sulphate ,are added. Aftershaking for 30 minutes the precipitated, 2 (p-amino benzene-.sulphonmethyl and crystallised from alcohol.

amide) pyridine is filtered off, washed with Water 'It melts at Example 22 9.6 grams of 6 amino-quinaldine is dissolved in 27 cc. of pyridine and 11.8 grams of p-nitro-benzene sulphonidacid-anhydride added. When the reaction is ccmpleteabout 50000. of water is added the precipitated 6-( p-.nitro-benzene sul- 'phonamido') quinaldine is filtere off and wa's'hed gradually added with stirring.

' .ent 483,945) is added. 1 When the reaction is complete the mixture is diluted with water and filtered, and the residual 2- (p-acetyl-benzyl-aminobenzene-sulphonamido) pyridine crystallised from alcohol. Melting point 177 C.

The acetyl compound on boiling with 30% sodium hydroxide solution for 12 hours and acidifying with acetic acid yields 2-(p-benzylaminoben- -zene-sulphon'amido) pyridine which after recrystallisation from alcohol melts at 200 C.

' Example 24 I e 9.7 grams of amino-isoquinoline is dissolved in 20 cc. of pyridine and 16 grams of p-acetylami- :no-benzene-sulphonyl chloride added, the temperature being kept below 50 C. When the reaction vis complete, water is added and the solid separated by filtration. After purification by dissolving in'aqueous alcoholic sodium hydroxide solution and precipitation by acidifying with acetic acid, crystalline l-(p-acetylamino-benzenesulphonamido)-isoquinoline, melting point 225 C., is obtained.

The acetyl compound on hydrolysis with 10 parts of boiling 2N sodium hydroxide solution for 1 hour, followed by acidification with acetic acid gives 1 (p-amino-benzenesulphonamido) iso- 1 quinoline.

Melting point 263- C.

7 Example 25 V 12.5 grams of 2- (p-amino-benzene-sulphonamido)-,pyridine isdissolved in-BO cc. of 2N sodium hydroxide solution and 40 cc. of benzyl chloride After standing for 1; hour 10060. of dry ether isadded, and the crude 2- (p-amino benzene sulphonbenzylamido)-pyridinefiltered off and extracted with 150 cc. of cold dilute hydrochloric acid. The residual 2 -(p-amino -:-benzene sulphonbenzyl amido)- pyridine is filtered ofi and recrystallised from al- .cohol.

It melts at 179 C.

' Example 26 r 7 grams of p diethylamino-azobenzene-p-sulphonyl chloride (prepared by the action of phosphorous pentachloride on sodium p-diethyl-amino-azo-benzene sulphonate) is added to 1.9 grams of 2-amino-pyridine dissolved in 20 cc. of pyridine and after the reaction is over water is added. The precipitated 2- (p diethyl aminoazobenzene-psulphonamido) -pyridine is filtered ofi, washed with water, and dissolved in parts of 2N sodium hydroxide solution. The solution is warmed to 30540. C. and solid sodium hydrosulphite'added .lgradually. until the red colour of the solution is discharged. Acteic acid 'is then added'until the solution is faintly acid; on concentration 2-(pamino -benzene sulphonamido) -pyridine separates, and is purified by recrystallisation from alcohol. Melting point 190 C.

Example 27 3'gralns of p-acetyl-amino-benzene sulphonyl chloride are suspended in 5 cc. of chloroform and '1 gramof 2-aminoepyridine dissolvedin v5.cc. of-

.from aqueous alcohol.

crystalline precipitate of 2-(p-amino-benzenep sulphonamido -pyridine is filtered off and recrystallised from acetone. It melts at 189-190 C.

Example 28 t A mixture of 4.6 grams of p-acetylamino-benzenesulphon-methylamide, melting point 183 C.

(obtained by the interaction of p-acetylamino- "benzene-sulphonyl chloride and aqueous methylamine), 3.2 grams of Z-bromopyridine, 2.8 grams of potassium carbonate and 0.2'gram of copper powder isheated at 200 Cffor 1 hour. The cooled melt is extracted with acetic acid and the filtered extract is concentrated whereupon 2-(p-acetylamino-benzene-sulphon methylamido) -pyridine separates. Crystallised from dilute acetic acid, it melt at 231 C. Hydrolysis by boiling for 1 hour with 10 parts of 2N sodium hydroxide gives on acidification with acetic acid 2- (p -amin0 -benzene-sulphonmethylamid0) -pyridine. Crystallised from alcohol it melts at 225 C.

' Example 29 25 grams of phenyl-2 amino-pyridine-5-sulphonic acid is suspended in cc. of pyridine and 24 grams of p-acetylamino-benzene-sulphonylchloride is added. After vheating'on a steam bath for 15 minutes, the mixture is diluted with 500 cc. of water and the precipitated phenyl-2(p-acetyamino-benzene sulphonamido) -pyridine-5 sulphonate is collected. Crystallised from 50% acetic acid it melts at -185" C.

V This ester on boiling for ,1 /2 hours with ten times its Weight of 2N sodium hydroxide solution and addition, with cooling, of hydrochloric acid until just-acid to Congo Red gives Z-(p-aminobenzene sulphonamido) pyridine 5-sulphonic acid. Melting point 305 C.

Example 30 mixture is boiled under reflux for 1 hour, the

acetone removed by distillation and the residue treated with water. The z-(p-acetylamino-ben- 'zene-sulphonamido) -pyridine so formed is collected. It melts at 224 C. when crystallised from aqueous alcohol.

Example 31 To 9.4 grams of 2-amino-pyridineat55 C. is added 11.6 grams of p-acetylamino-benzene-sulphonyl chloride. When the reaction is over the melt is dissolved in150 cc. of 2N sodium hydroxide' solution and the mixture is boiled under reflux for 1 hour. Acidification with acetic .acid precipitates 2 (peamino-benzene-sulphonamido) pyridine which melts at C. when crystallised 7 I Example 32 A mixture of'15.8 grams of 5- nitro-2 -chloropyridine, 21.4 grams of p-acetylamino-benzene sulphonamide, 13.5 grams of potassium carbonate (anhydrous) and 1.0 gram of copper powder is heated for 30 minutes at 180 C. The mixture is extracted with boiling water and filtered; acidification of the filtrate with acetic acid then gives -nitro 2 -(p-acetylamino-benzene-sulphonamido) -pyridine. Melting point 264 C.

Example 33 To a solution of 2.2 grams of 5-iodo-2-aminopyridine in '7 cc. of pyridine is added 2.4 grams of of p-acetylamino-benzene-sulphonyl chloride. When the reaction is over '70 cc. of water are added and the precipitate of 5-iodo-2-(p-acety1- amino-benzene-s-ulphonamido)-pyridine is collected, washed with water and crystallised from 50% acetic acid. Melting point 234 C. Hydrolysis of this with parts of 2N sodium hydroxide solution by boiling for 1 hour under reflux followed by addition of excess of 2N acetic acid gives 5-iodo-2- (p-aminobenzene-sulphonamido) pyridine. Purified by solution in boiling aqueous alcoholic sodium hydroxide followed by addition of boiling dilute acetic acid, it melts at 219 C.

Example 34 4.3 grams of 2-methylamino-pyridine is dissolved in cc. of pyridine and 9.5 grams of p-acetylamino benzene sulphonyl chloride is added. When the reaction mixture has cooled, 100 cc. of water are added and the precipitate of crude 2- (p-acetylamino-benzene-su1phonmethylamido -pyridine is collected, washed and crystallised from dilute acetic acid, Melting point Example 10 grams of 2-(p-aminobenzene-sulphonmethylamido) -pyridine (Example 21) is dissolved in cc. of 2N hydro-chloric acid and 10 cc. of acetic anhydride followed by suflicient saturated sodium acetate solution to remove Congo red acidity are added. The precipitate of z-(p-acetylamino benzene sulphonmethylamido) pyridine is collected, washed and crystallised from dilute acetic acid. Melting point 231 C.

What we claim and desire to secure by Letters Patent is:

1. 2- (p aminobenzene-sulphonamido) pyridine-5-su1phonic acid.

2. 2-(p-acetyl amino benzene sulfonamido) pyridines in which the pyridine ring is substituted. at a c-atom by the radical --SO3M in which M is a cation.

3. Sulianilyl Z-amino-pyridines in which the pyridine ring is substituted at a C-atom by the radical --SO3M in which M is a cation.

4. A compound of the formula in which X is hydrogen when Y is hydrogen, and in which X is acetyl when Y is phenyl.

5. Phenyl-2 (p-acetylamino-benzene sulphonamido) -pyridine-5-sulfonate ARTHUR JAMES EWINS. MONTAGUE ALEXANDER PHILLIPS. 

